Antigen-specific soluble helper molecules are produced during major histocompatibility complexdisparate allograft priming. Genetic mapping studies with appropriate recombinant and mutant lines of mice have defined the antigen specificities of the soluble helper molecules described here as being directed against the H-2Dd molecules. The production of antigen-specific helper molecules is a relatively early event after H-2Dd region allograft priming. Supernatants containing the antigen-specific helper molecules have no, or at least undetectable levels of, interleukin-2. Also, from the draining lymph nodes, we have demonstrated a later phase of factor production near the time of graft rejection which does contain nonspecific helper factors and IL-2.